Popp R A, Popp D M, Shinpock S G, Yang M Y, Mural J G, Aguinaga M P, Kopsombut P, Roa P D, Turner E A, Rubin E M
Biology Division, Oak Ridge National Laboratory, TN 37831, USA.
Blood. 1997 Jun 1;89(11):4204-12.
Hemoglobin (Hb) S Antilles is a naturally occurring form of sickling human Hb but causes a more severe phenotype than Hb S. Two homozygous viable Hb S Antilles transgene insertions from Tg58Ru and Tg98Ru mice were bred into MHOAH mice that express high oxygen affinity (P50 approximately 24.5 mm Hg) rather than normal (P50 approximately 40 mm Hg) mouse Hbs. The rationale was that the high oxygen affinity MHOAH Hb, the lower oxygen affinity of Hb S Antilles than Hb S (P50 approximately 40 v 26.5 mm Hg), and the lower solubility of deoxygenated Hb S Antilles than Hb S (approximately 11 v 18 g/dL) would favor deoxygenation and polymerization of human Hb S Antilles in MHOAH mouse red blood cells (RBCs). The Tg58 x Tg98 mice produced have a high and balanced expression (approximately 50% each) of h alpha and h beta(S Antilles) globins, 25% to 35% of their RBCs are misshapen in vivo, and in vitro deoxygenation of their blood induces 30% to 50% of the RBCs to form classical looking, elongated sickle cells with pointed ends. Tg58 x Tg98 mice exhibit reticulocytosis, an elevated white blood cell count and lung and kidney pathology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic intervention of sickle cell disease.
血红蛋白（Hb）S安的列斯型是人类镰状血红蛋白的一种自然存在形式，但比Hb S导致更严重的表型。将来自Tg58Ru和Tg98Ru小鼠的两个纯合可存活的Hb S安的列斯型转基因插入到表达高氧亲和力（P50约为24.5 mmHg）而非正常（P50约为40 mmHg）小鼠血红蛋白的MHOAH小鼠中。其原理是，高氧亲和力的MHOAH血红蛋白、Hb S安的列斯型比Hb S更低的氧亲和力（P50约为40对26.5 mmHg）以及脱氧Hb S安的列斯型比Hb S更低的溶解度（约为11对18 g/dL）将有利于人类Hb S安的列斯型在MHOAH小鼠红细胞（RBC）中脱氧和聚合。所产生的Tg58×Tg98小鼠具有hα和hβ（S安的列斯型）珠蛋白的高且平衡的表达（各约50%），其25%至35%的红细胞在体内呈畸形，并且其血液的体外脱氧诱导30%至50%的红细胞形成外观典型的、两端尖锐的细长镰状细胞。Tg58×Tg98小鼠表现出网织红细胞增多、白细胞计数升高以及镰状细胞病患者常见的肺和肾病理状况，这应使这些小鼠可用于镰状细胞病可能治疗干预的实验研究。
